In Three Hours' Time: TPA Administration Post-Stroke Onset

 As one of the leading causes of death in the United States, approach to stroke treatment and prognosis improvement has remained forefront in the medical community.

Stroke may present in two different forms - ischemic (blood supply is restricted to the brain via a clot in the peripheral venous system), or hemorrhagic (the rupture of a vessel within the brain itself). 

Tissue Plasminogen Activator (tPA) is a powerful clot-busting drug, and has proven to be a promising candidate for stroke treatment - if used within the correct time frame, that is (NIH, 2022). The drug acts within the fibrinolytic cascade to convert inactive plasminogen to its proteolytically active form, plasmin (Jilani, 2022). Plasmin, an endogenous fibrinolytic enzyme, acts by degrading fibrin clots (Hughes et. al, 2022). According to the FDA, tPA may be administered post-ischemic stroke no more than 4.5 hours post-symptom onset. Why? Unfortunately, the drug, however advantageous it may be within the gold-standard time window, has severe consequences if administered outside of this time. The main reason for this? Hemorrhagic transformation (HT) - the leakage of peripheral blood across the blood brain barrier, and into the brain (Pronk et. al, 2021). Sounds bad, but why are we concerned? Not only does this influx of blood into the space between the brain and skull lead to decreased oxygen flow to the brain and vital tissues, it could fatally increase intracranial pressure, further damaging the brain (Spronk et. al, 2021). The fact of the matter is this: if administered in the appropriate time window, tPA can have significant benefits, but if administered outside of this window, the risks of the drug outweigh the benefits.

Additionally, there are specific times by which tPA should never be give post-ischemic stroke. Some of these instances include:

• Patients with active internal bleeding (Jilani et. al, 2022)
• Patients with severe and uncontrolled hypertension (Jilani et. al, 2022)
• Patients who have undergone intracranial surgery or suffered serious head trauma within the last three months (Jilani et. al, 2022)

Efforts have been made to improve tPA administration effectiveness, whether it be via expansion of the administration window via other pharmaceuticals (Pena et. al, 2017), or via organized effort to reach, diagnose, and treat stroke victims earlier (UC Health, 2022) - both of these could provide distinct benefit to this patient population.

References:

NIH. (2022). Tissue Plasminogen Activator for Acute Ischemic Stroke (Alteplase, Activase). NINDS Contribution to Approved Therapies. Available from:https://www.ninds.nih.gov/about-ninds/impact/ninds-contributions-approved-therapies/tissue-plasminogen-activator-acute-ischemic-stroke-alteplase-activaser#:~:text=When%20administered%20quickly%20after%20stroke,of%20damage%20and%20functional%20impairment. 

Hughes, R., Tadi, P., Bollu, P. (2022). TPA Therapy. StatPearls. Available from: https://www.ncbi.nlm.nih,gov/books/NBK482376/ 

Jilani, T., Siddiqui, A. (2022). Tissue Plasminogen Activator. StatPearls. Available from: https://www.ncbi.nlm.nih.gov/books/NBK507917 

Pena, I., Borlongan, C., Shen, G., Davis, W. (2017). Strategies to Extend Thrombolytic Time Window for Ischemic Stroke Treatment: An Unmet Clinical Need. Journal of Stroke, 19(1), 50-60. https://doi.org/10.5853/jos.2016.01515 

Spronk, E., Sykes, G., Falcione, S., Munsterman, D., Joy, T., Kamtchum-Tatuene, J., Jickling, G. (2021). Hemorrhagic Transformation in Ischemic Stroke and the Role of Inflammation. Frontiers in Neurology 12. https://doi.org/10.3389/fneur.2021.661955 

Mobile stroke treatment unit. UCHealth. (2022, May 12). Retrieved November 28, 2022, from https://www.uchealth.org/treatments-procedures/mobile-stroke-treatment-unit/